A central question that arose from the successful use of the BCR-ABL targeted agent imatinib in CML is whether the leukemic stem cell can be eradicated. Rapid relapse that is observed upon cessation of the drug suggested that the leukemic stem cell was at most only mildly affected by drug therapy. In this paper, the investigators present a model based upon the effects of imatinib on BCR-ABL transcripts in patients treated with the drug. This model hypothesizes that imatinib has an effect on the proliferating BCR-ABL positive cells by inducing degradation and then has a declining percentage of transcript positive cells by reducing stem cell numbers. The model predicts that many of the stem cells are in a dormant state, possibly because of their interaction with the microenvironment, and are then not susceptible to the drug. Their prediction is that relapse is associated with rapid release and growth of the leukemic stem cell from this population. Their model allows for a prediction that moving cells into a more frequent cycling state may make them more responsive to imatinib and that by reducing the stem cell pool, the rapid relapse that is observed on removing the drug may be abrogated. Resistance forms part of their model as well — it fits with introduction of resistant clones early as well as late emergence of imatinib-resistant clones. The investigators propose that the leukemic stem cell can eventually be eradicated by continuous long-term treatment with imatinib unless mutations that result in drug resistance occur. The investigators propose that stem cells may be eradicated by moving stem cells into a proliferative compartment. Resistance remains the main foe, and it may appear early so that some stem cells cannot be eradicated.
In Brief
Directing future targets in a disease such as CML remains important because of continual need for the drug and relapse in its absence. The model generated from the two patient populations examined in this manuscript present a contrast to the hypothesis on the behavior of the BCR-ABL positive CML in the manuscript by Michor et. al1 . Both manuscripts put forth models for behavior of hematopoietic stem cells based upon in vivo data and observations that focus on the biphasic decline in BCR transcripts on the initiation of imatinib therapy. Where the two manuscripts differ is on the question of whether the hematopoietic stem cell can be a target for imatinib. In the manuscript by Michor, the rapid relapse rate is attributed to the stem cell not being sensitive to chemotherapy. In the model presented in this paper, the investigators propose that it is not chemotherapy insensitivity but rather location of the stem cell in an environment or stage that is quiescent so that it is only slowly responsive to therapy. This distinction is important because moving toward therapy that targets the stem cell is different in these two models. The model here would favor inducing proliferation or movement from one niche to another to more rapidly affect the stem cell, whereas the manuscript by Michor and colleagues suggests that a different approach may be required to target the stem cell. The proof may be in the introduction of an additional therapy, and it remains to be seen whether this should be early, or later after initiation of imatinib.
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Competing Interests
Dr. Petruzzelli indicated no relevant conflicts of interest.
